Effects of monoamine depletion on the ketamine-induced locomotor activity of preweanling, adolescent, and adult rats: Sex and age differences

Abstract

Ketamine significantly increases the locomotor activity of rodents, however this effect varies according to the sex and age of the animal being tested. To determine the role monoamine systems play in ketamine's locomotor activating effects: (a) male and female preweanling, adolescent, and adult rats were pretreated with vehicle or the monoamine depleting agent reserpine (1 or 5 mg/kg), and (b) the behavioral actions of ketamine (20 or 40 mg/kg) were then compared to Damphetamine (2 mg/kg) and cocaine (10 or 15 mg/kg). The ability of reserpine to deplete dorsal striatal dopamine (DA) and serotonin (5-HT) in male and female rats was determined using HPLC. Ketamine caused substantial increases in the locomotion of preweanling rats and older female rats (adolescents and adults), but had only small stimulatory effects on adolescent and adult male rats. When compared to cocaine and D -amphetamine, ketamine was especially sensitive to the locomotor-inhibiting effects of monoamine depletion. Ketamine-induced locomotion is at least partially mediated by monoamine systems, since depleting DA and 5-HT levels by 87-96% significantly attenuated the locomotor activating effects of ketamine in male and female rats from all three age groups. When administered to reserpine-pretreated rats, ketamine produced a different pattern of behavioral effects than either psychostimulant, suggesting that ketamine does not stimulate locomotor activity via actions at the presynaptic terminal. Instead, our results are consistent with the hypothesis that ketamine increases locomotor activity through a down-stream mechanism, possibly involving ascending DA and/or 5-HT projection neurons.

(R,S)-ketamine and (2R,6R)-hydroxynorketamine differentially affect memory as a function of dosing frequency

“…The repeated administration of ketamine has served as an attractive model for conditions that are characterized by dissociative symptoms and cognitive impairment that are due to NMDAR hypofunction (e.g., schizophrenia [ 18 , 50 , 71 ]), often assayed preclinically as a deficit in NOR performance [ 72 ]. Interestingly, the acute hyperlocomotor response to ketamine that is triggered by NMDAR inhibition is more pronounced in preweanlings [ 73 ] and adolescents [ 74 , 75 ] relative to adults, and in females relative to males, especially during adolescence [ 76 , 77 ]. One interpretation of these observations is that younger rodents and females have an enhanced sensitivity to the NMDAR-inhibition-dependent actions of ketamine.…”

“…If the recognition memory impairment we observed were due principally to NMDAR inhibition by ketamine, then our results would have mirrored this pattern of enhanced sensitivity in younger rodents and females. The fact that they did not suggest that these locomotor differences arise from distinctions in monoaminergic signaling downstream of NMDAR inhibition [ 73 , 76 ], or alternatively, that the recognition impairments are not due to NMDAR inhibition. Consistent with the latter, we also observed recognition deficits following repeated ( 2R,6R )-HNK administration, a finding that suggests that sustained elevations in glutamate release, independent of NMDAR blockade or glutamatergic network disinhibition [ 37 ], is sufficient to alter explicit memory in NOR.…”

Effects of dopamine and serotonin synthesis inhibitors on the ketamine-, d-amphetamine-, and cocaine-induced locomotor activity of preweanling and adolescent rats: sex differences

“…Moreover, there is equivocal evidence suggesting that PCPA may reduce the locomotor activating effects of MK-801 in male adult rats and mice [38]. As in our companion paper [43], male and female rats were also tested with doses of D-amphetamine (2 mg/kg) and cocaine (15 mg/kg) known to produce robust locomotor activity in rats of these ages [47][48][49]. These groups were included for comparison purposes, because there is evidence that ketamine may function like a psychostimulant at the presynaptic terminal [16,50,51; but see 52].…”

“…At the time of behavioral testing (i.e., 2 h after the final AMPT injection), rats (n = 10 per group) were injected with saline or ketamine (5,10,20, or 40 mg/kg, ip). A broad dose range of ketamine was used because male and female rats are differentially responsive to this drug [21,22,25,26,43,64]. Immediately after saline/ketamine injections, rats were placed in the testing chamber and locomotor activity, which was operationally defined as distance traveled (cm), was measured continuously across 12 ten-minute time blocks (2 h).…”

“…Indeed, antagonists at D1 and D2 receptors, as well as 5-HT 2A receptors, significantly reduce the hyperactivity caused by ketamine and MK-801 [16,[32][33][34][35][36][37][38][39][40][41][42]. Using a different approach (i.e., a monoamine depletion strategy), Crawford et al [43] showed that a dose of reserpine (5 mg/kg) sufficient to reduce dorsal striatal DA and 5-HT levels by 87-96% caused a significant decline in the ketamineinduced locomotor activity of male and female preweanling, adolescent, and adult rats. Similar results were reported when reserpine-treated adult male rats and mice were injected with MK-801 or PCP [33,34,[44][45][46].…”